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Bilateral Clear Cell Papillary Cystadenoma of the Epididymides Presenting as Infertility: An Early Manifestation of Von Hippel-lindau’s Syndrome
0022-5347/85 /1336-1062$02.00 /0 Vol. 133, June Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1985 by The Williams & Wilkins Co.
BILATERAL CLEAR CELL PAPILLARY CYSTADENOMA OF THE EPIDIDYMIDES PRESENTING AS INFERTILITY: AN EARLY MANIFESTATION OF VON HIPPEL-LINDAU'S SYNDROME FREDERICK R. WITTEN,* DAVID P. O'BRIEN, III,t CHARLES W. SEWELL JOSEPH K. WHEATLEY
AND
From the Departments of Surgery (Urology) and Patlwlogy, Emory University Sclwol of Medicine, Atlanta, Georgia
ABSTRACT
Papillary cystadenoma of the epididymis is a rare benign tumor, accounting for only 4 per cent of all epididymal tumors. Histologically, it can be confused with metastatic renal cell carcinoma. We report a case of bilateral involvement of the epididymides and infertility. Its diagnostic significance is its association with the von Rippel-Lindau syndrome, necessitating close surveillence. Tumors of the epididymis are reported infrequently and symptomatic epididymal tumors are rare. Of the epididymal tumors 75 per cent are considered benign and papillary cystadenomas account for only 5 per cent of these benign tumors. Although rarely symptomatic with conservative treatment indicated, the medical implications of papillary cystadenoma are great. CASE REPORT
A 24-year-old white man was evaluated for primary infertility. There was no history of epididymal or testicular trauma, infection or other associated urogenital abnormalities. The only medical history of interest involved removal of a cerebellar hemangioblastoma several years previously. Physical examination, including funduscopy, was normal except for the genitalia. The testes were bilaterally normal in size and consistency. Nontender, firm, slightly nodular masses were noted by inspection and palpation of the globus major of both epididymides (fig. 1, A). Otherwise, the spermatic cords and adnexa were normal. A routine semen analysis revealed azoospermia. Transscrotal exploration was done to obtain epididymal and testicular biopsies, and to perform reconstructive procedures to restore fertility if possible. The globus major bilaterally consisted of fibrous, grayish-red masses, with multiple tiny cysts (fig. 1, B). There were no indications of a patent ductus epididymis or the presence of sperm on microsurgical dissection. - Histologically, sections from the right and left epididymides demonstrated identical lesions. Cystic dilatation and ectasia of the efferent ducts were widespread and varied from slight microscopic enlargement of the ducts to grossly observed cysts. These ducts were filled with a homogeneous eosinophilic material that resembled the colloid seen in thyroid follicles (fig. 2, A). The normal epithelial lining of the channels was replaced by cuboidal to columnar cells with prominent clear or vacuolated cytoplasm. The nuclei were small and inconspicuous, and demonstrated no mitoses or dysplastic features. Frequently, these clear cells showed marked hyperplasia with protrusion of papillary processes into the luminal space (fig. 2, B). In some areas the process virtually had replaced the lumen of the duct and resembled a well differentiated renal cell carcinoma. Biopsies of both testes demonstrated active spermatogenesis, with a moderate decrease in mature spermatozoa. A spermatid Accepted for publication February 13, 1985. Read at annual meeting of Southeastern Section, American Urological Association, Haines City, Florida, March 20-23, 1983. * Current address: 201 Baptist East Doctors Building, 3950 Kresge Way, Louisville, Kentucky 40207. t Requests for reprints: Emory University Clinic, 1365 Clifton Rd., N. E., Atlanta, Georgia 30322.
count revealed decreased numbers, averaging less than 20 spermatids per tubule. DISCUSSION
Primary tumors of the epididymis are reported infrequently. Less than 5 per cent of the 1,039 intrascrotal tumors recorded in Great Britain between 1958 and 1967 involved the epididymis and spermatic cord. 1 Broth and associates reviewed the literature in 1968 and found 278 reported cases of epididymal tumors. 2 Of these tumors 75 per cent were benign and 25 per cent were malignant. The adenomatoid tumor was the most common benign epididymal tumor, representing 78 per cent of the cases. 2 It has been estimated that male subjects have only a 1 in 1 million chance of having an extratesticular tumor. 1 Papillary clear cell cystadenoma of the epididymis is a rare, benign tumor first described in 1956 by Sherrick.3 A review of the literature indicates only 42 cases reported previously. 1• 4 •5 This tumor is thought to account for 4 per cent of all epididymal tumors. 2 It has been suggested that this tumor originates from the epididymis or nearby mullerian duct remnants, such as the appendix testes, aberrant ducts or paradidymis, or from the wolffian duct remnants, such as the appendix epididymis. Sherrick thought that the cystadenoma arose from the lining of a spermatocele. 3 Grant and Hoffman indicated a mesonephric origin of these tumors from within the efferent ducts of the epididymis. 6 Using electron microscopic observations Tsuda and associates determined the origin of papillary cystadenoma in 3 cases to be the efferent ducts.7 The mesonephric origin of these tumors has led some investigators to postulate a female counterpart arising from the vesicular appendage, paroophoron, duct of the epoophoron and Gartner's duct remnant, all of which are remnants of the mesonephric duct. 8 Most investigators now believe that papillary cystadenoma of the globus major develops from within the duct system of the ductuli efferentes, and is the only epididymal tumor with a purely epithelial character. 1• 7 Although usually only a few centimeters long and firm with small fluid-filled cysts, as in our patient, cystadenomas may become quite large and predominantly cystic.8 Microscopically, they appear as delicate papillary tumors filling the ducts. Grant and Hoffman observed 3 stages of the tumor in 1 patient, which progressed from hy:perplasia to adenoma with early stromal invasion. 6 The tumor may become so extensive that it fills the ducts and obliterates the cystic spaces, giving the appearance of stromal invasion and a pattern difficult to separate from metastatic renal cell carcinoma. Histologically, as in our case, the papillary lesions consist of a fibrovascular stroma lined by cuboidal to tall columnar epithelium, with a clear, indistinctly vacuolated cytoplasm. The
1062
BILATERAL PAPILLARY CYSTADENOMA OF EPIDIDYMIDES
1063
FIG. 1. A, bilateral firm, nontender, slightly nodular epididymal masses (arrows). B, surfaces of epididymides were bosselated and corresponded to areas of gross cyst formation (arrows) alternating with denser fibrous stroma.
FIG. 2. A, complex papillary structures protrude into lumen of ectatic duct. Remainder of lumen contains homogeneous eosinophilic material. B, papillary structures and cystic spaces are lined by cuboidal to columnar cells with clear or vacuolated cytoplasm.
nuclei are oval to round and normochromic. The cystic spaces are lined by a single layer of cuboidal to flattened epithelium supported by a fibrous wall of various thickness. Bilateral papillary clear cell cystadenoma of the epididymides is rare, having occurred in 25 to 30 per cent of the previously reported cases of cystadenoma. 6 • 7 · 9 • 10 An abnormal semen analysis has been documented in 4 cases with bilateral lesions. 6 • 7 • 10 Of these patients 2 were azoospermic. 7 Only 1 previously reported patient was evaluated initially for infertility. 10 The diagnostic significance of cystadenoma of the epididymis lies in its association with the von Hippel-Lindau syndrome. Cerebellar hemangioblastoma occurs in 36 to 60 per cent of the cases and is the most frequent cause of morbidity. 11 It may lead to progressive neurological impairment and death in up to 53 per cent of the patients. 11 Through autopsy records of patients with von Hippel-Lindau's syndrome, Horton and associates demonstrated an incidence of renal cell carcinoma in 45 per cent and an associated 32. per cent mortality. 11 Papillary cystadenoma represents the epididymal component of Lindau's disease. Price reported on 5 patients with bilateral papillary cystadenoma, 4 of whom had lesions in other organs consistent with an incomplete form of von Hippel-Lindau's syndrome. 9 Tsuda and associates described familial bilateral papillary cystadenoma in 3 brothers, 1 of whom had other characteristics of von Hippel-Lindau's syndrome. 7 In addition, 10 to 40 per cent of the patients with known von HippelLindau's syndrome may be expected to have epididymal involvement. 9 • 11 Although the risk of developing other characteristics of the von Rippel-Lindau syndrome seems to be much greater with bilateral epididymal cystadenomas, unilateral tumors also have been described with the syndrome. 9 • 12 As might be expected,
infertility may prove to be an early manifestation of von Hippe!-Lindau' s syndrome in the younger patient with bilateral epididymal involvement. More serious sequelae of cerebellar hemangioblastoma, pheochromocytoma and renal cell carcinoma seem to occur later, the mean age at diagnosis being 31, 34 and 41 years, respectively. 11 Christenson and associates, 13 and deTure 14 have indicated the urological implications of this syndrome and have stressed the necessity of close surveillance, including routine use of the computerized tomography (CT) scan. A subsequent excretory urogram and CT scan revealed bilateral simple cysts in our patient who previously was found to have a cerebellar hemangioblastoma typical of the von Hippel-Lindau syndrome. REFERENCES
l. Elsasser, E.: Tumors of the epididymis. Rec. Res. Cancer Res., 60:
163, 1977. 2. Broth, G., Bullock, W. K. and Morrow, J.: Epididymal tumors: l. Report of 15 new cases including review of literature. 2. Histochemical study of the so-called adenomatoid tumor. J. Urol., 100: 530, 1968. 3. Sherrick, J. C.: Papillary cystadenoma of the epididymis. Cancer, 9: 403, 1956. 4. Gruber, M. B., Healey, G. B., Toguri, A.G. and Warren, M. M.: Papillary cystadenoma of the epididymis: component of von Rippel-Lindau syndrome. Urology, 16: 305, 1980. 5. Civil, I. D. S. and Hackett, A. H.: Papillary cystadenoma of the epididymis: a case report. Aust. New Zeal. J. Surg., 51: 304, 1981.
6. Grant, S. M. and Hoffman, E. F.: Bilateral papillary adenomas of the epididymides. Arch. Path., 76: 620, 1963. 7. Tsuda, H., Fukushima, S., Takahashi, M., Hikosaka, Y. and Hayashi, K.: Familial bilateral papillary cystadenoma of the
1064
8. 9. 10. 11.
WITTEN AND ASSOCIATES
epididymis: report of three cases in siblings. Cancer, 37: 1831, 1976. Chan, Y.-H., Shinella, R. A. and Draper, J. W.: Papillary clear cell cystadenoma of the epididymis. J. Urol., 100: 661, 1968. Price, E. B., Jr.: Papillary cystadenoma of the epididymis. A clinicopathologic analysis of 20 cases. Arch. Path., 91: 456, 1971. Crisp, J. C. and Roberts, P. F.: A case of bilateral cystadenoma of the epididymides presenting as infertility. Brit. J. Urol., 47: 682, 1975. Horton, W. A., Wong, V. and Eldridge, R.: Von Hippel-Lindau
disease: clinical and pathological manifestations in nine families with 50 affected members. Arch. Intern. Med., 136: 769, 1976. 12. Goodbody, R. A. and Gamlen, T. R.: Cerebellar haemangioblastoma and genitourinary tumours. J. Neurol. Neurosurg. Psych., 37: 606, 1974. 13. Christenson, P. J., Craig, J.P., Bibro, M. C. and O'Connell, K. J.: Cysts containing renal cell carcinoma in von Hippel- Lindau disease. J. Urol., 128: 798, 1982. 14. deTure, F. A.: Urologic implications of von Hippel-Lindau syndrome. Urology, 11: 612, 1978.
THE JOURNAL OF UROLOGY
Copyright © 1985 by The Williams & Wilkins Co.
BILATERAL CLEAR CELL PAPILLARY CYSTADENOMA OF THE EPIDIDYMIDES PRESENTING AS INFERTILITY: AN EARLY MANIFESTATION OF VON HIPPEL-LINDAU'S SYNDROME FREDERICK R. WITTEN,* DAVID P. O'BRIEN, III,t CHARLES W. SEWELL JOSEPH K. WHEATLEY
AND
From the Departments of Surgery (Urology) and Patlwlogy, Emory University Sclwol of Medicine, Atlanta, Georgia
ABSTRACT
Papillary cystadenoma of the epididymis is a rare benign tumor, accounting for only 4 per cent of all epididymal tumors. Histologically, it can be confused with metastatic renal cell carcinoma. We report a case of bilateral involvement of the epididymides and infertility. Its diagnostic significance is its association with the von Rippel-Lindau syndrome, necessitating close surveillence. Tumors of the epididymis are reported infrequently and symptomatic epididymal tumors are rare. Of the epididymal tumors 75 per cent are considered benign and papillary cystadenomas account for only 5 per cent of these benign tumors. Although rarely symptomatic with conservative treatment indicated, the medical implications of papillary cystadenoma are great. CASE REPORT
A 24-year-old white man was evaluated for primary infertility. There was no history of epididymal or testicular trauma, infection or other associated urogenital abnormalities. The only medical history of interest involved removal of a cerebellar hemangioblastoma several years previously. Physical examination, including funduscopy, was normal except for the genitalia. The testes were bilaterally normal in size and consistency. Nontender, firm, slightly nodular masses were noted by inspection and palpation of the globus major of both epididymides (fig. 1, A). Otherwise, the spermatic cords and adnexa were normal. A routine semen analysis revealed azoospermia. Transscrotal exploration was done to obtain epididymal and testicular biopsies, and to perform reconstructive procedures to restore fertility if possible. The globus major bilaterally consisted of fibrous, grayish-red masses, with multiple tiny cysts (fig. 1, B). There were no indications of a patent ductus epididymis or the presence of sperm on microsurgical dissection. - Histologically, sections from the right and left epididymides demonstrated identical lesions. Cystic dilatation and ectasia of the efferent ducts were widespread and varied from slight microscopic enlargement of the ducts to grossly observed cysts. These ducts were filled with a homogeneous eosinophilic material that resembled the colloid seen in thyroid follicles (fig. 2, A). The normal epithelial lining of the channels was replaced by cuboidal to columnar cells with prominent clear or vacuolated cytoplasm. The nuclei were small and inconspicuous, and demonstrated no mitoses or dysplastic features. Frequently, these clear cells showed marked hyperplasia with protrusion of papillary processes into the luminal space (fig. 2, B). In some areas the process virtually had replaced the lumen of the duct and resembled a well differentiated renal cell carcinoma. Biopsies of both testes demonstrated active spermatogenesis, with a moderate decrease in mature spermatozoa. A spermatid Accepted for publication February 13, 1985. Read at annual meeting of Southeastern Section, American Urological Association, Haines City, Florida, March 20-23, 1983. * Current address: 201 Baptist East Doctors Building, 3950 Kresge Way, Louisville, Kentucky 40207. t Requests for reprints: Emory University Clinic, 1365 Clifton Rd., N. E., Atlanta, Georgia 30322.
count revealed decreased numbers, averaging less than 20 spermatids per tubule. DISCUSSION
Primary tumors of the epididymis are reported infrequently. Less than 5 per cent of the 1,039 intrascrotal tumors recorded in Great Britain between 1958 and 1967 involved the epididymis and spermatic cord. 1 Broth and associates reviewed the literature in 1968 and found 278 reported cases of epididymal tumors. 2 Of these tumors 75 per cent were benign and 25 per cent were malignant. The adenomatoid tumor was the most common benign epididymal tumor, representing 78 per cent of the cases. 2 It has been estimated that male subjects have only a 1 in 1 million chance of having an extratesticular tumor. 1 Papillary clear cell cystadenoma of the epididymis is a rare, benign tumor first described in 1956 by Sherrick.3 A review of the literature indicates only 42 cases reported previously. 1• 4 •5 This tumor is thought to account for 4 per cent of all epididymal tumors. 2 It has been suggested that this tumor originates from the epididymis or nearby mullerian duct remnants, such as the appendix testes, aberrant ducts or paradidymis, or from the wolffian duct remnants, such as the appendix epididymis. Sherrick thought that the cystadenoma arose from the lining of a spermatocele. 3 Grant and Hoffman indicated a mesonephric origin of these tumors from within the efferent ducts of the epididymis. 6 Using electron microscopic observations Tsuda and associates determined the origin of papillary cystadenoma in 3 cases to be the efferent ducts.7 The mesonephric origin of these tumors has led some investigators to postulate a female counterpart arising from the vesicular appendage, paroophoron, duct of the epoophoron and Gartner's duct remnant, all of which are remnants of the mesonephric duct. 8 Most investigators now believe that papillary cystadenoma of the globus major develops from within the duct system of the ductuli efferentes, and is the only epididymal tumor with a purely epithelial character. 1• 7 Although usually only a few centimeters long and firm with small fluid-filled cysts, as in our patient, cystadenomas may become quite large and predominantly cystic.8 Microscopically, they appear as delicate papillary tumors filling the ducts. Grant and Hoffman observed 3 stages of the tumor in 1 patient, which progressed from hy:perplasia to adenoma with early stromal invasion. 6 The tumor may become so extensive that it fills the ducts and obliterates the cystic spaces, giving the appearance of stromal invasion and a pattern difficult to separate from metastatic renal cell carcinoma. Histologically, as in our case, the papillary lesions consist of a fibrovascular stroma lined by cuboidal to tall columnar epithelium, with a clear, indistinctly vacuolated cytoplasm. The
1062
BILATERAL PAPILLARY CYSTADENOMA OF EPIDIDYMIDES
1063
FIG. 1. A, bilateral firm, nontender, slightly nodular epididymal masses (arrows). B, surfaces of epididymides were bosselated and corresponded to areas of gross cyst formation (arrows) alternating with denser fibrous stroma.
FIG. 2. A, complex papillary structures protrude into lumen of ectatic duct. Remainder of lumen contains homogeneous eosinophilic material. B, papillary structures and cystic spaces are lined by cuboidal to columnar cells with clear or vacuolated cytoplasm.
nuclei are oval to round and normochromic. The cystic spaces are lined by a single layer of cuboidal to flattened epithelium supported by a fibrous wall of various thickness. Bilateral papillary clear cell cystadenoma of the epididymides is rare, having occurred in 25 to 30 per cent of the previously reported cases of cystadenoma. 6 • 7 · 9 • 10 An abnormal semen analysis has been documented in 4 cases with bilateral lesions. 6 • 7 • 10 Of these patients 2 were azoospermic. 7 Only 1 previously reported patient was evaluated initially for infertility. 10 The diagnostic significance of cystadenoma of the epididymis lies in its association with the von Hippel-Lindau syndrome. Cerebellar hemangioblastoma occurs in 36 to 60 per cent of the cases and is the most frequent cause of morbidity. 11 It may lead to progressive neurological impairment and death in up to 53 per cent of the patients. 11 Through autopsy records of patients with von Hippel-Lindau's syndrome, Horton and associates demonstrated an incidence of renal cell carcinoma in 45 per cent and an associated 32. per cent mortality. 11 Papillary cystadenoma represents the epididymal component of Lindau's disease. Price reported on 5 patients with bilateral papillary cystadenoma, 4 of whom had lesions in other organs consistent with an incomplete form of von Hippel-Lindau's syndrome. 9 Tsuda and associates described familial bilateral papillary cystadenoma in 3 brothers, 1 of whom had other characteristics of von Hippel-Lindau's syndrome. 7 In addition, 10 to 40 per cent of the patients with known von HippelLindau's syndrome may be expected to have epididymal involvement. 9 • 11 Although the risk of developing other characteristics of the von Rippel-Lindau syndrome seems to be much greater with bilateral epididymal cystadenomas, unilateral tumors also have been described with the syndrome. 9 • 12 As might be expected,
infertility may prove to be an early manifestation of von Hippe!-Lindau' s syndrome in the younger patient with bilateral epididymal involvement. More serious sequelae of cerebellar hemangioblastoma, pheochromocytoma and renal cell carcinoma seem to occur later, the mean age at diagnosis being 31, 34 and 41 years, respectively. 11 Christenson and associates, 13 and deTure 14 have indicated the urological implications of this syndrome and have stressed the necessity of close surveillance, including routine use of the computerized tomography (CT) scan. A subsequent excretory urogram and CT scan revealed bilateral simple cysts in our patient who previously was found to have a cerebellar hemangioblastoma typical of the von Hippel-Lindau syndrome. REFERENCES
l. Elsasser, E.: Tumors of the epididymis. Rec. Res. Cancer Res., 60:
163, 1977. 2. Broth, G., Bullock, W. K. and Morrow, J.: Epididymal tumors: l. Report of 15 new cases including review of literature. 2. Histochemical study of the so-called adenomatoid tumor. J. Urol., 100: 530, 1968. 3. Sherrick, J. C.: Papillary cystadenoma of the epididymis. Cancer, 9: 403, 1956. 4. Gruber, M. B., Healey, G. B., Toguri, A.G. and Warren, M. M.: Papillary cystadenoma of the epididymis: component of von Rippel-Lindau syndrome. Urology, 16: 305, 1980. 5. Civil, I. D. S. and Hackett, A. H.: Papillary cystadenoma of the epididymis: a case report. Aust. New Zeal. J. Surg., 51: 304, 1981.
6. Grant, S. M. and Hoffman, E. F.: Bilateral papillary adenomas of the epididymides. Arch. Path., 76: 620, 1963. 7. Tsuda, H., Fukushima, S., Takahashi, M., Hikosaka, Y. and Hayashi, K.: Familial bilateral papillary cystadenoma of the
1064
8. 9. 10. 11.
WITTEN AND ASSOCIATES
epididymis: report of three cases in siblings. Cancer, 37: 1831, 1976. Chan, Y.-H., Shinella, R. A. and Draper, J. W.: Papillary clear cell cystadenoma of the epididymis. J. Urol., 100: 661, 1968. Price, E. B., Jr.: Papillary cystadenoma of the epididymis. A clinicopathologic analysis of 20 cases. Arch. Path., 91: 456, 1971. Crisp, J. C. and Roberts, P. F.: A case of bilateral cystadenoma of the epididymides presenting as infertility. Brit. J. Urol., 47: 682, 1975. Horton, W. A., Wong, V. and Eldridge, R.: Von Hippel-Lindau
disease: clinical and pathological manifestations in nine families with 50 affected members. Arch. Intern. Med., 136: 769, 1976. 12. Goodbody, R. A. and Gamlen, T. R.: Cerebellar haemangioblastoma and genitourinary tumours. J. Neurol. Neurosurg. Psych., 37: 606, 1974. 13. Christenson, P. J., Craig, J.P., Bibro, M. C. and O'Connell, K. J.: Cysts containing renal cell carcinoma in von Hippel- Lindau disease. J. Urol., 128: 798, 1982. 14. deTure, F. A.: Urologic implications of von Hippel-Lindau syndrome. Urology, 11: 612, 1978.